tbuckley/cabot-search huggingface dataset:
Growing Pains: The Need for Engineered Platforms to Study Growth Plate Biology
Authors: Aleczandria S. Tiffany, Brendan A. C. Harley
Journal: Advanced Healthcare Materials (2022)

Growth plates, or physis, are highly specialized cartilage tissues responsible for longitudinal bone growth in children and adolescents. Chondrocytes that reside in growth plates are organized into three distinct zones essential for proper function. Modeling key features of growth plates may provide an avenue to develop advanced tissue engineering strategies and perspectives for cartilage and bone regenerative medicine applications and a platform to study processes linked to disease progression. In this review, a brief introduction of the growth plates and their role in skeletal development is first provided. Injuries and diseases of the growth plates as well as physiological and pathological mechanisms associated with remodeling and disease progression are discussed. Growth plate biology, namely, its architecture and extracellular matrix organization, resident cell types, and growth factor signaling are then focused. Next, opportunities and challenges for developing 3D biomaterial models to study aspects of growth plate biology and disease in vitro are discussed. Finally, opportunities for increasingly sophisticated in vitro biomaterial models of the growth plate to study spatiotemporal aspects of growth plate remodeling, to investigate multicellular signaling underlying growth plate biology, and to develop platforms that address key roadblocks to in vivo musculoskeletal tissue engineering applications are described.
Quantifying the impact of gut microbiota on inflammation and hypertensive organ damage
Authors: Ellen G Avery, Hendrik Bartolomaeus, Ariana Rauch, Chia-Yu Chen, Gabriele N’Diaye, Ulrike Löber, Theda U P Bartolomaeus, Raphaela Fritsche-Guenther, André F Rodrigues, Alex Yarritu, Cheng Zhong, Lingyan Fei, Dmitry Tsvetkov, Mihail Todiras, Joon-Keun Park, Lajos Markó, András Maifeld, Andreas Patzak, Michael Bader, Stefan Kempa, Jennifer A Kirwan, Sofia K Forslund, Dominik N Müller, Nicola Wilck
Journal: Cardiovascular Research (2022)

Abstract Aims Hypertension (HTN) can lead to heart and kidney damage. The gut microbiota has been linked to HTN, although it is difficult to estimate its significance due to the variety of other features known to influence HTN. In the present study, we used germ-free (GF) and colonized (COL) littermate mice to quantify the impact of microbial colonization on organ damage in HTN. Methods and results 4-week-old male GF C57BL/6J littermates were randomized to remain GF or receive microbial colonization. HTN was induced by subcutaneous infusion with angiotensin (Ang) II (1.44 mg/kg/day) and 1% NaCl in the drinking water; sham-treated mice served as control. Renal damage was exacerbated in GF mice, whereas cardiac damage was more comparable between COL and GF, suggesting that the kidney is more sensitive to microbial influence. Multivariate analysis revealed a larger effect of HTN in GF mice. Serum metabolomics demonstrated that the colonization status influences circulating metabolites relevant to HTN. Importantly, GF mice were deficient in anti-inflammatory faecal short-chain fatty acids (SCFA). Flow cytometry showed that the microbiome has an impact on the induction of anti-hypertensive myeloid-derived suppressor cells and pro-inflammatory Th17 cells in HTN. In vitro inducibility of Th17 cells was significantly higher for cells isolated from GF than conventionally raised mice. Conclusion The microbial colonization status of mice had potent effects on their phenotypic response to a hypertensive stimulus, and the kidney is a highly microbiota-susceptible target organ in HTN. The magnitude of the pathogenic response in GF mice underscores the role of the microbiome in mediating inflammation in HTN.
Precisely Targeted Nano‐Controller of PD‐L1 Level for Non‐Small Cell Lung Cancer Spinal Metastasis Immunotherapy
Authors: Lei Zhou, Haifeng Liang, Yuxiang Ge, Wang Ding, Qing Chen, Taiwei Zhang, Lan Xiao, Yulin Li, Jian Dong, Xiaowen He, Fengfeng Xue, Libo Jiang
Journal: Advanced Healthcare Materials (2022)

Although immune checkpoint inhibitors (ICIs) have been widely applied to treat non-small cell lung cancer (NSCLC), a significant proportion of patients, especially those with spinal metastasis (NSCLC-SM), are insensitive to anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) ICIs. A drug delivery nano-controller of PD-L1 that targets NSCLC-SM can solve this problem, however, none have been developed to date. In this study, it is shown that integrin β3 (β3-int) is strongly upregulated in NSCLC-SM. Its inhibitor RGDyK promotes PD-L1 ubiquitination, indicating the potential application of RGDyK as a new PD-L1 inhibitor in nano-controller and a targeting peptide for NSCLC-SM treatment. According to the synergistic effect of photodynamic therapy and ICIs on T-cell activation through the release of tumor antigens, RGDyK-modified and zinc protoporphyrin (ZnPP)-loaded mesoporous silicon nanoparticles (ZnPP@MSN-RGDyK) are fabricated. The ZnPP@MSN-RGDyK nanoparticles precisely target β3-int to inhibit PD-L1, exhibiting high photodynamic therapy efficiency, and excellent immunotherapeutic effects in an NSCLC-SM mouse model. Collectively, the findings indicate that ZnPP@MSN-RGDyK is a promising immunotherapeutic agent for treating NSCLC-SM.
Regulation of NETosis and Inflammation by Cyclophilin D in Myeloperoxidase‐Positive Antineutrophil Cytoplasmic Antibody–Associated Vasculitis
Authors: Takashi Kudo, Daigo Nakazawa, Kanako Watanabe‐Kusunoki, Masatoshi Kanda, Satoka Shiratori‐Aso, Nobuya Abe, Saori Nishio, Jun‐ichiro Koga, Sari Iwasaki, Takahiro Tsuji, Yuichiro Fukasawa, Miwako Yamasaki, Masahiko Watanabe, Sakiko Masuda, Utano Tomaru, Masaaki Murakami, Yasuaki Aratani, Akihiro Ishizu, Tatsuya Atsumi
Journal: Arthritis & Rheumatology (2022)

Objective Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) is pathologically characterized by focal fibrinoid necrosis, in which ANCA‐mediated neutrophil extracellular trap (NET) formation and subsequent endothelial cell necrosis occur. Cyclophilin D (CypD) plays an important role in mediation of cell necrosis and inflammation via the opening of mitochondrial permeability transition pores. This study was undertaken to examine the role of CypD in AAV pathogenesis. Methods We assessed the role and mechanism of CypD in ANCA‐stimulated neutrophils in vitro by immunostaining and electron microscopy observation. We performed a comprehensive RNA‐sequencing analysis on ANCA‐treated murine neutrophils. To investigate the role of CypD in vivo, we assessed disease features in CypD‐knockout mice and wild‐type mice using 2 different murine AAV models: anti‐myeloperoxidase IgG transfer–induced AAV and spontaneous AAV. Results In vitro experiments showed that pharmacologic and genetic inhibition of CypD suppressed ANCA‐induced NET formation via the suppression of reactive oxygen species and cytochrome c release from the mitochondria. RNA‐sequencing analyses in ANCA‐treated murine neutrophils revealed the involvement of inflammatory responses, with CypD deficiency reducing ANCA‐induced alterations in gene expression. Furthermore, analyses of upstream regulators revealed the relevance of intracellular calcium (CypD activator) and cyclosporin (CypD inhibitor) in ANCA stimulation, indicating that the CypD‐dependent opening of mitochondrial permeability transition pores is associated with ANCA‐induced neutrophil activation and NETosis. In both AAV mouse models, the genetic deletion of CypD ameliorated crescentic glomerulonephritis via the inhibition of CypD‐dependent neutrophil and endothelial necrosis. Conclusion CypD targeting is a novel and specific therapeutic strategy for AAV via the resolution of necrotizing vasculitis.
Keep an Eye on the Back: Spondyloarthritis in Patients With Acute Anterior Uveitis
Authors: Judith Rademacher, Hanna Müllner, Torsten Diekhoff, Hildrun Haibel, Sabrina Igel, Dominika Pohlmann, Fabian Proft, Mikhail Protopopov, Valeria Rios Rodriguez, Murat Torgutalp, Uwe Pleyer, Denis Poddubnyy
Journal: Arthritis & Rheumatology (2022)

This study was undertaken to analyze the prevalence of spondyloarthritis (SpA) in patients with acute anterior uveitis (AAU), to identify parameters associated with the presence of SpA, and to evaluate the performance of referral algorithms for identifying patients with a high probability of having SpA.Prospectively recruited consecutive patients with noninfectious AAU underwent structured rheumatologic assessment including magnetic resonance imaging of the sacroiliac joints, allowing a definitive diagnosis/exclusion of concomitant SpA. Fisher's exact test and Mann-Whitney U test were used to compare AAU patients with SpA and AAU patients without SpA. Furthermore, logistic regression analyses were performed. The predictive performance of SpA referral strategies was analyzed by calculating the sensitivity, specificity, positive predictive value, and positive and negative likelihood ratios.Among the 189 AAU patients evaluated, 106 (56%) were diagnosed as having SpA. The majority of SpA patients (93%) had predominantly axial SpA and 7 patients had peripheral SpA. In 74 patients (70%), the SpA diagnosis was established for the first time. In multivariable logistic regression analysis, psoriasis (odds ratio [OR] 12.5 [95% confidence interval (95% CI) 1.3-120.2]), HLA-B27 positivity (OR 6.3 [95% CI 2.4-16.4]), elevated C-reactive protein level (OR 4.8 [95% CI 1.9-12.4]), and male sex (OR 2.1 [95% CI 1.1-4.2]) were associated with the presence of SpA. None of the ophthalmologic parameters were found to be predictive of SpA. The Dublin Uveitis Evaluation Tool (DUET) showed higher specificity for SpA recognition than the Assessment of SpondyloArthritis international Society (ASAS) tool for the early referral of patients with a suspected diagnosis of axial SpA (specificity for SpA 42% versus 28%), whereas the sensitivity of the ASAS tool was slightly higher than the DUET tool (sensitivity for SpA 80% versus 78%). However, more than 20% of the AAU patients in this study who were diagnosed as having SpA would have been missed by both referral strategies.Our study revealed a high prevalence of SpA in AAU patients overall, as well as a high prevalence of previously undiagnosed SpA in AAU patients. Therefore, we propose rheumatologic evaluation for all AAU patients with musculoskeletal symptoms.
What should a health and social care workforce strategy look like?
Authors: Billy Palmer
Journal: BMJ (2022)

<h3>Aims:</h3> To analyse the outcome of small margin (up to 2 mm) excision of primary clinically well-defined periocular basal cell carcinomas (BCCs). <h3>Methods:</h3> Retrospective evaluation of 90 well-demarcated primary BCCs having a minimum follow-up of 36 months. All patients underwent excision of the tumour with maximum margins of 2 mm. Resulting defects were, if possible, closed directly. Reconstruction of defects requiring flaps or grafts was delayed until receipt of the histological report which was obtained in all cases. <h3>Results:</h3> One-stage excision and direct closure was performed in 67 patients (74.4%). In 23 patients (25.6%) reconstruction was delayed by 4 days to enable receipt of the histopathology report. Histological assessment confirmed complete excision after the first excision in 78 (86.7%) rising to 83 (92.2%) after two excisions. The mean follow-up was 47.5 (SD 9.1) months. Of the 12 cases with incompletely excised lesions, seven of the patients chose not to have any more surgery, and only one of these recurred. There were two other recurrences, and in both of them the lesion had initially been reported as completely excised. Overall the recurrence rate in our study was 3.3% (n = 3). <h3>Conclusions:</h3> Our recurrence rate compares well with published results following conventional excision of BCCs. In the absence of availability of Mohs surgery, well-demarcated nodular basal cell carcinomas can be safely excised using smaller margins than conventionally practised.
Trends and Distribution of In-Hospital Mortality Among Pregnant and Postpartum Individuals by Pregnancy Period
Authors: Lindsay K. Admon, Nicole D. Ford, Jean Y. Ko, Cynthia Ferre, Charlan D. Kroelinger, Katy B. Kozhimannil, Elena V. Kuklina
Journal: JAMA Network Open (2022)

This cross-sectional study investigates trends in death rates and proportion of deaths by pregnancy period among pregnant and postpartum individuals from 1994 to 2019.
Liquefied Microcapsules Compartmentalizing Macrophages and Umbilical Cord‐Derived Cells for Bone Tissue Engineering
Authors: Sara Nadine, Inês Fernandes, Sónia G. Patrício, Clara R. Correia, João F. Mano
Journal: Advanced Healthcare Materials (2022)

Abstract Extraordinary capabilities underlie the potential use of immune cells, particularly macrophages, in bone tissue engineering. Indeed, the depletion of macrophages during bone repair often culminates in disease scenarios. Inspired by the native dynamics between immune and skeletal systems, this work proposes a straightforward in vitro method to bioengineer biomimetic bone niches using biological waste. For that, liquefied and semipermeable reservoirs generated by electrohydrodynamic atomization and layer‐by‐layer techniques are developed to coculture umbilical cord‐derived human cells, namely monocyte‐derived macrophages, mesenchymal‐derived stromal cells (MSCs), and human umbilical vein endothelial cells (HUVECs). Poly(ε‐caprolactone) microparticles are also added to the liquefied core to act as cell carriers. The fabricated microcapsules grant the successful development of viable microtissues, ensuring the high diffusion of bioactive factors. Interestingly, macrophages within the bioengineered microcapsules increase the release of osteocalcin, osteoprotegerin, and vascular endothelial growth factor. The cytokines profile variation indicates macrophages' polarization into a prohealing phenotype. Altogether, the incorporation of macrophages within the fabricated microcapsules allows to recreate an appropriate bone microenvironment for developing new bone mineralized microtissues. The proposed bioencapsulation protocol is a powerful self‐regulated system, which might find great applicability in bone tissue engineering based on bottom‐up approaches or disease modeling.
Impaired Proteolysis of Noncanonical RAS Proteins Drives Clonal Hematopoietic Transformation
Authors: Sisi Chen, Rahul S. Vedula, Antonio Cuevas-Navarro, Bin Lu, Simon J. Hogg, Eric Wang, Salima Benbarche, Katherine Knorr, Won Jun Kim, Robert F. Stanley, Hana Cho, Caroline Erickson, Michael Singer, Dan Cui, Steven Tittley, Benjamin H. Durham, Tatiana S. Pavletich, Elise Fiala, Michael F. Walsh, Daichi Inoue, Sebastien Monette, Justin Taylor, Neal Rosen, Frank McCormick, R. Coleman Lindsley, Pau Castel, Omar Abdel-Wahab
Journal: Cancer Discovery (2022)

Abstract Recently, screens for mediators of resistance to FLT3 and ABL kinase inhibitors in leukemia resulted in the discovery of LZTR1 as an adapter of a Cullin-3 RING E3 ubiquitin ligase complex responsible for the degradation of RAS GTPases. In parallel, dysregulated LZTR1 expression via aberrant splicing and mutations was identified in clonal hematopoietic conditions. Here we identify that loss of LZTR1, or leukemia-associated mutants in the LZTR1 substrate and RAS GTPase RIT1 that escape degradation, drives hematopoietic stem cell (HSC) expansion and leukemia in vivo. Although RIT1 stabilization was sufficient to drive hematopoietic transformation, transformation mediated by LZTR1 loss required MRAS. Proteolysis targeting chimeras (PROTAC) against RAS or reduction of GTP-loaded RAS overcomes LZTR1 loss-mediated resistance to FLT3 inhibitors. These data reveal proteolysis of noncanonical RAS proteins as novel regulators of HSC self-renewal, define the function of RIT1 and LZTR1 mutations in leukemia, and identify means to overcome drug resistance due to LZTR1 downregulation. Significance: Here we identify that impairing proteolysis of the noncanonical RAS GTPases RIT1 and MRAS via LZTR1 downregulation or leukemia-associated mutations stabilizing RIT1 enhances MAP kinase activation and drives leukemogenesis. Reducing the abundance of GTP-bound KRAS and NRAS overcomes the resistance to FLT3 kinase inhibitors associated with LZTR1 downregulation in leukemia. This article is highlighted in the In This Issue feature, p. 2221
The UK government’s “personal responsibility” policy for covid is hypocritical and unsustainable
Authors: Stephen Reicher, Susan Michie, Robert West
Journal: BMJ (2022)

<h3>Abstract</h3> Pressure injuries are classified as chronic wounds, but the reasons for poor healing are not well understood, such as whether impairments are due to comorbidities and bacteria. Chronic vascular ulcers have pathologies caused by extracellular release of hemoglobin, so we questioned whether muscle pressure injuries (mPI) would have intrinsic pathologies due to extracellular myoglobin (Mb), and whether iron chelation therapy could improve them. Healthy mice in specific-pathogen-free conditions received pressure injuries. Cohorts were Mb–/– versus Mb+/+ in elderly 20-month-olds, or adult Mb+/+ 5-month-olds treated with saline versus iron chelator (subcutaneous deferoxamine, DFO). For comparison, healthy control regeneration was created using cardiotoxin injection. Unlike acute injuries, the wound bed of mPI displayed failure of phagocytosis at day 3, accompanied by high accumulation of iron, oxidative damage, and a lack of viable immune cells. The necrotic tissue was later expelled as slough (eschar). Mb-knockout mPI had undetectable levels of iron, low oxidative stress (p&lt;0.05), greater immune infiltration (230%, p&lt;0.05), 4-fold decreased marker for extracellular traps (p&lt;0.01), and 50% smaller area of tissue death. Similar to knockout, injecting DFO after wounding caused improvement in oxidative stress (2-fold, p&lt;0.05), extracellular trap marker (4-fold, p&lt;0.01), and diameter of tissue killed (35%, p&lt;0.05). In other words, tissue margins could be protected from dying. At later timepoints, DFO-treated wounds had higher levels of viable immune infiltrate (p&lt;0.05), greater extent of muscle regeneration (46% smaller diameter of gap, p&lt;0.01), and superior myofiber morphology (p&lt;0.0001). We conclude that myoglobin iron from mPI causes oxidative stress and delayed infiltration, despite a lack of infection. Remarkably, tissue viability could be salvaged by post-injury treatment with subcutaneous injections of an FDA-approved iron chelator. This work also sheds light on how a hostile wound microenvironment impairs myogenesis and morphogenesis.
This Month’s Highlights
Journal: Journal of the American Society of Nephrology (2022)

Our aim was to evaluate the role of SPECT/CT for the diagnosis of diabetic foot infection by labeled leukocytes. <b>Methods:</b> Seventeen patients with 19 clinically suspected sites of infection were included. After leukocyte labeling and administration, planar scans were acquired at 30 min, 4 h, and 24 h for 18 consecutive patients. SPECT/CT was obtained at 6 h. The final diagnosis was established by clinical follow-up (24 mo) in all cases and by bone biopsy for 14 sites. <b>Results:</b> Leukocyte scanning was positive in 16 of 19 lesions and negative in 3. SPECT/CT changed the interpretation of the planar and SPECT images for 10 of 19 suspected sites (52.6%): it excluded osteomyelitis in 6 cases, revealed bone infection in 1 case, and revealed both bone and soft-tissue infection in 3 cases. The hybrid device did not significantly contribute to the evaluation of patients with negative scan results. <b>Conclusion:</b> SPECT/CT can be useful for a more accurate diagnosis of diabetic foot infection by labeled leukocyte imaging.
Conducting Polymer‐ECM Scaffolds for Human Neuronal Cell Differentiation
Authors: Chiara Barberio, Janire Saez, Aimee Withers, Malavika Nair, Francesco Tamagnini, Roisin M. Owens
Journal: Advanced Healthcare Materials (2022)

Abstract 3D cell culture formats more closely resemble tissue architecture complexity than 2D systems, which are lacking most of the cell–cell and cell–microenvironment interactions of the in vivo milieu. Scaffold‐based systems integrating natural biomaterials are extensively employed in tissue engineering to improve cell survival and outgrowth, by providing the chemical and physical cues of the natural extracellular matrix (ECM). Using the freeze–drying technique, porous 3D composite scaffolds consisting of poly(3,4‐ethylene‐dioxythiophene) doped with polystyrene sulfonate (PEDOT:PSS), containing ECM components (i.e., collagen, hyaluronic acid, and laminin) are engineered for hosting neuronal cells. The resulting scaffolds exhibit a highly porous microstructure and good conductivity, determined by scanning electron microscopy and electrochemical impedance spectroscopy, respectively. These supports boast excellent mechanical stability and water uptake capacity, making them ideal candidates for cell infiltration. SH‐SY5Y human neuroblastoma cells show enhanced cell survival and proliferation in the presence of ECM compared to PEDOT:PSS alone. Whole‐cell patch‐clamp recordings acquired from differentiated SHSY5Y cells in the scaffolds demonstrate that ECM constituents promote neuronal differentiation in situ. These findings reinforce the usability of 3D conducting supports as engineered highly biomimetic and functional in vitro tissue‐like platforms for drug or disease modeling.
Repeat Dynamics across Timescales: A Perspective from Sibling Allotetraploid Marsh Orchids (<i>Dactylorhiza majalis</i> s.l.)
Authors: Mimmi C Eriksson, Terezie Mandáková, Jamie McCann, Eva M Temsch, Mark W Chase, Mikael Hedrén, Hanna Weiss-Schneeweiss, Ovidiu Paun
Journal: Molecular Biology and Evolution (2022)

Abstract To provide insights into the fate of transposable elements (TEs) across timescales in a post-polyploidization context, we comparatively investigate five sibling Dactylorhiza allotetraploids (Orchidaceae) formed independently and sequentially between 500 and 100K generations ago by unidirectional hybridization between diploids D. fuchsii and D. incarnata. Our results first reveal that the paternal D. incarnata genome shows a marked increased content of LTR retrotransposons compared to the maternal species, reflected in its larger genome size and consistent with a previously hypothesized bottleneck. With regard to the allopolyploids, in the youngest D. purpurella both genome size and TE composition appear to be largely additive with respect to parents, whereas for polyploids of intermediate ages we uncover rampant genome expansion on a magnitude of multiple entire genomes of some plants such as Arabidopsis. The oldest allopolyploids in the series are not larger than the intermediate ones. A putative tandem repeat, potentially derived from a non-autonomous miniature inverted-repeat TE (MITE) drives much of the genome dynamics in the allopolyploids. The highly dynamic MITE-like element is found in higher proportions in the maternal diploid, D. fuchsii, but is observed to increase in copy number in both subgenomes of the allopolyploids. Altogether, the fate of repeats appears strongly regulated and therefore predictable across multiple independent allopolyploidization events in this system. Apart from the MITE-like element, we consistently document a mild genomic shock following the allopolyploidizations investigated here, which may be linked to their relatively large genome sizes, possibly associated with strong selection against further genome expansions.